Sickle Cell Disease and Gene Therapy: A Novel Treatment Approach

This poster presentation discusses sickle cell disease and gene therapy as a novel treatment approach. It covers the basics of SCD, diagnosis, and limitations of current treatments. The poster also explores the latest research on gene therapy, including CRISPR technology and zinc finger nucleases, and their potential to replace defective genes associated with haemoglobin production. The benefits and limitations of gene therapy for SCD are also discussed.

Poster presentation
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SICKLE CELL DISEASE AND GENE THERAPY- A NOVEL TREATMENT APPROACH
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Introduction
Sickle cell disease (SCD) refers to blood disorders that are inherited from the parents. Sickle cell anemia is the
most common type of SCD.
This is usually manifested in the form of an abnormality in the protein haemoglobin that is responsible for
carrying oxygen in the body. The problems in SCD naturally begin about 5 to 6 months (Piel, Steinberg and
Rees 2017).
The condition usually occurs under circumstances when an individual is found to inherit abnormal copies of
haemoglobin, one copy from each parent. The haemoglobin gene is present on chromomose 11 ( Gravitz and
Pincock 2014).
There are a range of subtypes of the gene that vary depending on the mutations that occur. Several factors that
are responsible for triggering these mutations are stress, temperature alterations, high altitude and dehydration.
Symptoms of sickle cell disease usually do not appear in a person who has single abnormal gene copy. These
people are commonly referred to as carriers.
Materials and Methods
In SCD, conducting a complete blood count helps in revealing the haemoglobin levels. Levels ranging from 6–
8 g/dl with high reticulocyte count demonstrates presence of sickle cell disease. The major symptoms of the
disease are as follows:
Presence of a yellow coloured skin (jaundice) and whitening of the eyes (icterus)
Fussiness or fatigue
Painful swelling in feet and hands, known as dactylitis.
These symptoms are commonly accompanied by pain that can strike in different regions of the body such as
the arms, abdomen, lower back, chest, and legs. Other health complications are related to aplastic crisis,
trapping of the blood vessels in the spleen, infections, brain complications, and acute chest syndrome.
Diagnosis
SCD is usually diagnosed by a doctor depending on the results that are obtained from a range of screening
tests.
Early diagnosis among children helps in preventing future complications. In screening programs that are
conducted upon new borns, blood is collected from heel prick in spots that are present on special papers.
The hemoglobin collected from the blood is then examined in laboratories. The results of newborn
screening are sent to the physician for assessing the presence or absence of SCD in the child ( Klings et al.
2014).
Hydroxycarbamide, also referred to as hydroxyurea is a medication that is
principally used in the treatment of chronic myelogenous leukemia, cervical
cancer, sickle-cell disease, and polycythemia vera.
The primary mechanism of action via the inhibition of ribonucleotide
reductase enzyme (Ware et al. 2016). This is usually accomplished by
foraging tyrosyl free radicals that are associated with decrease of
nucleoside diphosphates (NDPs).
Hydroxyurea is useful in the management of SCD by increasing the fetal
haemoglobin concentration (Aygun et al. 2013). This is achieived by an
elevation in the levels of nitric oxide that result in activation of guanylyl
cyclase with a subsequent increase in cyclic GMP levels.
The basic approach was grounded on the incorporation of DNA into engineered viruses for
delivering DNA into chromosomes. Recent studies have focused on the use of CRISPR technology
and zinc finger nucleases that focus on knocking out of the defective genes and replacing them in
the chromosome of interest.
Results
Olowoyeye and Okwundu (2016) conducted a review to demonstrate the safety and efficacy of gene
therapy in SCD treatment on prevention of symptoms and survival. However, no trials were found
by the authors that reported replacement of faulty genes associated with haemoglobin production
with normal ones.
Another study that reported first patient subjected to treatment with lentiviral vector–mediated
adding of antisickling β-globin gene in autologous hematopoietic stem cell suggested presence of
adverse events that were constant with busulfan conditioning. The levels of antisickling β-globin
were high, 15 months following the therapy, without relapse of SCD (figure 1) (Ribeil et al. 2017).
According to Hoban, Orkin and Bauer (2016) significant development has been made in gene
therapy treatment of SCD. The γ-retroviral vectors, novel genome engineering, next-generation
lentiviral vectors, and gene regulation methods share the objective of stopping erythrocyte
sickling. The skill to direct either homologous or non-homologous joining end joining pathway to
give predictable alterations holds major therapeutic relevance for SCD (figure 2).
Findings from another study suggested that transcription activator‐like effector nucleases (TALENs)
are a novel gene editing tool that can replace the SCD mutation in hiPSCs derived from patients. In
association with piggyback transposon, the gene targeting did not leave any residual ectopic
sequences at correction site and the modified hiPSCs retained complete pluripotency with normal
karyotype (Sun and Zhao 2014).
Hydroxyurea
Conclusion
SCD is an inherited blood disorder
Hydroyurea is an oral medication that targets the reduces the
synthesis of deoxyribonucleotides.
Gene therapy is gaining wide attention in the field of research
It hs the capability of replacing defective and damaged sickle cells
Limitations
Lack of adequate studies on safety of gene therapy techniques fail to
establish reliability and validity of the results
More human trials should be conducted using the CRISPR technology
to eradicate SCD from affected people.
References
Aygun, B., Mortier, N.A., Smeltzer, M.P., Shulkin, B.L., Hankins, J.S. and Ware,
R.E., 2013. Hydroxyurea treatment decreases glomerular hyperfiltration in
children with sickle cell anemia. American journal of hematology, 88(2), pp.116-
119.
Ginn, S.L., Alexander, I.E., Edelstein, M.L., Abedi, M.R. and Wixon, J., 2013.
Gene therapy clinical trials worldwide to 2012–an update. The journal of gene
medicine, 15(2), pp.65-77.
Gravitz, L. and Pincock, S., 2014. Sickle-cell disease. Nature, 515(7526), pp.S1-
S1.
Hoban, M.D., Orkin, S.H. and Bauer, D.E., 2016. Genetic treatment of a molecular
disorder: gene therapy approaches to sickle cell disease. Blood, pp.blood-2015.
Klings, E.S., Machado, R.F., Barst, R.J., Morris, C.R., Mubarak, K.K., Gordeuk,
V.R., Kato, G.J., Ataga, K.I., Gibbs, J.S., Castro, O. and Rosenzweig, E.B., 2014.
An official American Thoracic Society clinical practice guideline: diagnosis, risk
stratification, and management of pulmonary hypertension of sickle cell
disease. American journal of respiratory and critical care medicine, 189(6),
pp.727-740.
Piel, F.B., Steinberg, M.H. and Rees, D.C., 2017. Sickle cell disease. New
England Journal of Medicine, 376(16), pp.1561-1573.
Ribeil, J.A., Hacein-Bey-Abina, S., Payen, E., Magnani, A., Semeraro, M.,
Magrin, E., Caccavelli, L., Neven, B., Bourget, P., El Nemer, W. and Bartolucci,
P., 2017. Gene therapy in a patient with sickle cell disease. New England Journal
of Medicine, 376(9), pp.848-855.
Sun, N. and Zhao, H., 2014. Seamless correction of the sickle cell disease
mutation of the HBB gene in human induced pluripotent stem cells using
TALENs. Biotechnology and bioengineering, 111(5), pp.1048-1053.
Ware, R.E., Davis, B.R., Schultz, W.H., Brown, R.C., Aygun, B., Sarnaik, S.,
Odame, I., Fuh, B., George, A., Owen, W. and Luchtman-Jones, L., 2016.
Hydroxycarbamide versus chronic transfusion for maintenance of transcranial
doppler flow velocities in children with sickle cell anaemia—TCD With
Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label,
phase 3, non-inferiority trial. The Lancet, 387(10019), pp.661-670.
Wirth, T., Parker, N. and Ylä-Herttuala, S., 2013. History of gene
therapy. Gene, 525(2), pp.162-169.
Doctors also hold the capability of diagnosing SCD before the birth of a child.
This is usually done by extraction of amniotic fluid, the fluid present in the
amnion that surrounds a foetus, or tissue obtained from placenta, the organ that is
responsible for attaching the umbilical cord to womb of the mother.
Testing SCD prior to birth can be conducted during 8-10 weeks of pregnancy.
This testing locates the gene for sickle haemoglobin.
Gene therapy
This refers to the technique that encompasses the use of genes for
preventing or treating a disease. It can be defined as the therapeutic delivery
of genetic components into the cells, with the aim of compensating the
presence of abnormal genes and their subsequent defects in the body.
The first attempt at altering the human DNA was performed by Martin
Cline in 1980 (Wirth, Parker and Ylä-Herttuala 2013). Clinical trials that
attempted to use gene therapy for the treatment of SCD were started in
2014.
The primary approach adopted by the technique of gene therapy is the
administration of DNA to the damaged or defective cells that either disrupt
or express a protein (Ginn et al. 2013).
Figure 1- Result of SCD specific red
cell assay (Ribeil et al. 2017)
Figure 2- Strategies for gene therapy for SCD
(Hoban, Orkin and Bauer 2016)
Figure I- Difference between healthy cell and sickle cell
(Source- www.yourgenome.org)